Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients Wth Facial Acne Two Phase 3 Randomized Clinical Trials

(1)

Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne

Two Phase 3 Randomized Clinical Trials

Adelaide Hebert, MD; Diane Thiboutot, MD; Linda Stein Gold, MD; Martina Cartwright, PhD; Mara Gerloni, PhD;

Enrico Fragasso, MS; Alessandro Mazzetti, MD

IMPORTANCEAcne is a common, multifactorial skin condition, and treatments with novel mechanisms have been elusive.

OBJECTIVETo assess the safety and efficacy of clascoterone cream, 1%, a novel topical androgen receptor inhibitor, in 2 phase 3 randomized clinical trials (CB-03-01/25 and CB-03-01/26).

DESIGN, SETTING, AND PARTICIPANTSTwo identical, multicenter, randomized,

vehicle-controlled, double-blind, phase 3 studies conducted from November 2015 to April 2018 evaluated the efficacy and safety of use of clascoterone cream, 1%, in males and nonpregnant females 9 years and older with moderate or severe facial acne as scored on the Investigator’s Global Assessment scale. Participants were enrolled if they had 30 to 75 inflammatory lesions and 30 to 100 noninflammatory lesions.

INTERVENTIONSPatients were randomized to treatment with clascoterone cream, 1%, or vehicle cream and applied approximately 1 g to the whole face twice daily for 12 weeks.

MAIN OUTCOMES AND MEASURESTreatment success was defined as an Investigator’s Global Assessment score of 0 (clear) or 1 (almost clear), and a 2-grade or greater improvement from baseline and absolute change from baseline in noninflammatory and inflammatory lesion counts at week 12. Safety measures included adverse event frequency and severity.

RESULTSA total of 1440 patients were randomzied in 2 studies. In CB-03-01/25, 353 participants were randomized to treatment with clascoterone cream, 1% (median [range]

age, 18.0 [10-58] years; 221 [62.6%] female), and 355 participants were randomized to treatment with vehicle cream (median [range] age, 18.0 [9-50] years; 215 (60.6%) female); in CB-03-01/26, 369 participants were randomized to treatment with clascoterone cream, 1%

(median [range] age, 18.0 [10-50] years; 243 [65.9%] female), and 363 participants were randomized to treatment with vehicle cream (median [range] age, 18.0 [range, 11-42] years;

221 [60.9%] female). At week 12, treatment success rates in CB-03-01/25 and CB-03-01/26 with clascoterone cream, 1%, were 18.4% (point estimate, 2.3; 95% CI, 1.4-3.8; P < .001) and 20.3% (point estimate, 3.7; 95% CI, 2.2-6.3; P < .001) vs 9.0% and 6.5% with vehicle, respectively. At week 12, in both CB-03-01/25 and CB-03-01/26, treatment with clascoterone cream, 1%, resulted in a significant reduction in absolute noninflammatory lesions from baseline to −19.4 (point estimate difference, −6.4; 95% CI, −10.3 to −2.6; P < .001) and −19.4 (point estimate difference, −8.6; 95% CI, −12.3 to −4.9; P < .001) vs −13.0 and −10.8 with vehicle, respectively, as well as a reduction in inflammatory lesions from baseline to −19.3 (point estimate difference, −3.8; 95% CI, −6.4 to −1.3; P < .001) and −20.0 (point estimate difference, −7.4; 95% CI, −9.8 to −5.1; P < .001) vs −15.5 and −12.6 with vehicle, respectively.

Adverse events rates were low and mostly mild; the predominant local skin reaction was trace or mild erythema.

CONCLUSIONS AND RELEVANCEUse of clascoterone cream, 1%, for acne treatment appears to demonstrate favorable efficacy and safety with low adverse event rates.

TRIAL REGISTRATIONClinicalTrials.gov Identifiers:NCT02608450andNCT02608476

JAMA Dermatol. doi:10.1001/jamadermatol.2020.0465 Published online April 22, 2020.

Editorial

Supplemental content

Author Affiliations: McGovern Medical School, The University of Texas Health Science Center, Houston (Hebert); College of Medicine, The Pennsylvania State University, Hershey (Thiboutot);

Henry Ford Health System, Detroit, Michigan (Stein Gold); Cassiopea Inc, San Diego, California (Cartwright);

Cassiopea SpA, Lainate, Italy (Gerloni, Fragasso, Mazzetti).

Corresponding Author: Alessandro Mazzetti, MD, Cassiopea SpA, Via Cristoforo Colombo 1, 20020 Lainate, Italy ([email protected]).

JAMA Dermatology | Original Investigation

(2)

A

cne is the eighth most prevalent disease in the world¹ and affects more than 640 million people globally.²The onset of acne often coincides with pubertal hormonal changes,³and the condition affects approximately 85% of adolescents and young adults aged 12 to 25 years.³However, acne can also persist into, or develop during, adulthood.⁴Novel therapeutic innovations for the treatment of acne have been sparse in recent years, with no new mechanism of action in- troduced and approved by the US Food and Drug Administra- tion (FDA) since isotretinoin in 1982.⁵

Acne is a multifactorial condition characterized by ex- cess sebum production, epithelial hyperkeratinization, Cutibacterium acnes colonization in the pilosebaceous unit, and inflammation.⁶Current first-line treatments targeting 1 or 2 aspects of acne pathophysiology include benzoyl peroxide, topical retinoids, and topical or oral antibiotics.^7-9Antibiotic resistance in acne is a concern.¹⁰Oral isotretinoin, which may be used for more severe cases, affects multiple acnegenic pathways. Although efficacious for the treatment of acne, it is associated with adverse effects and must be used with caution in females of childbearing age owing to known teratogenicity.^7-9,11Females with acne can be treated with a combined oral contraceptive (COC) or spironolactone,^7-9,12both of which affect androgens.^9,12

Androgen receptors (ARs) are expressed throughout the skin and are found in the sebaceous glands, sebocytes, and dermal papilla cells.¹³Circulating and locally (skin) synthesized androgens such as testosterone and dihydrotestosterone (DHT) bind to the AR and stimulate sebum production in both males and females.^12-14

Androgen inhibition is an effective strategy for the treatment of acne in females. Certain COCs (eg, norgestimate, norethindrone) are approved by the FDA to treat acne in females^15-17; these drugs suppress androgen production, thereby reducing circulating androgens.^12,17Spironolactone is an aldosterone inhibitor and AR blocker^12,18that is used off label to treat acne in females.^18,19

Both COCs and spironolactone are associated with systemic adverse effects, are contraindicated in pregnancy, and are unsuitable for use in males with acne.^9,12Other AR inhibi- tors and/or antiandrogens have not been approved for the treatment of acne in males.

Topical clascoterone cream, 1% (cortexolone 17α- propionate), a new chemical entity, is a novel topical androgen receptor inhibitor under investigation as a first-in-class therapy for the treatment of acne in both males and females.^20,21In vitro studies suggest that clascoterone com- petes with androgens, specifically DHT, for binding to the androgen receptor, thereby inhibiting downstream signaling of acnegenic pathways.^20,21Reduced transcription of androgen- responsive genes inhibits sebum production and activation of inflammatory pathways, including those involved in proin- flammatory cytokine synthesis.²¹In this way, clascoterone targets more than 1 acnegenic pathway. Clascoterone targets androgen receptors at the site of application and is quickly metabolized to an inactive form, thus limiting systemic activity.²⁰The proposed mechanism of action of clascoterone is shown in Figure 1.^6,13,20-24

An early proof-of-concept study²⁵revealed that topical clascoterone cream, 1%, is well tolerated and clinically more effective than vehicle and tretinoin, 0.05%. Phase 2 studies demonstrated the safety and tolerability of clascoterone cream, 1%, in adolescents and adults with acne vulgaris and estab- lished clascoterone cream, 1%, used twice daily as the best regimen for phase 3 development.^26,27Herein, we describe 2 identical phase 3 studies evaluating the efficacy and safety of topical clascoterone cream, 1%, vs vehicle cream applied twice daily for 12 weeks in patients with facial acne vulgaris.

Methods

Trial Design

The CB-03-01/25 and CB-03-01/26 trials were identical, multicenter, randomized, double-blind, vehicle-controlled, par- allel-group phase 3 comparison studies of the efficacy and safety of topical clascoterone cream, 1%. These studies were designed according to the FDA’s industry guidelines for estab- lishing effectiveness of drugs intended for treatment of acne vulgaris.²⁸

Study CB-03-01/25 was carried out at 45 sites in the United States (n = 502), 7 sites in Ukraine (n = 132), and 3 sites in the Republic of Georgia (n = 74). Study CB-03-01/26 was conducted at 10 sites in the United States (n = 93), 8 sites in Bul- garia (n = 90), 9 sites in Romania (n = 186), 12 sites in Poland (n = 222), 3 sites in Serbia (n = 39), and 6 sites in the Republic of Georgia (n = 102).

Study approval was obtained from the relevant ethics com- mittees, institutional review boards, and national central au- thorities for all study sites. The studies were conducted in accordance with the Declaration of Helsinki. Voluntary informed consent/assent forms were signed by every patient and/or their parent or guardian. The protocols were approved by the FDA.

Patients

Male and nonpregnant female patients 9 years or older with moderate to severe facial acne vulgaris (grade 3 or 4 on the Investigator’s Global Assessment [IGA] scale) were eligible for enrollment. Patients had at least 30 to a maximum of 75

Key Points

QuestionWhat is the efficacy and safety of clascoterone cream, 1%, in the treatment of facial acne among patients older than 9 years?

FindingsResults of 2 phase 3 randomized clinical trials including 1440 patients demonstrated that patients with acne treated with clascoterone cream, 1%, experienced greater treatment success vs treatment with vehicle, with considerable reductions in absolute noninflammatory and inflammatory lesion counts. Adverse events with use of clascoterone cream, 1%, were predominantly mild and similar to those with use of vehicle.

MeaningClascoterone cream, 1%, a novel topical androgen receptor inhibitor, appears to demonstrate a favorable safety profile and improvement in efficacy for acne treatment.

(3)

inflammatory lesions and at least 30 to a maximum of 100 noninflammatory lesions. Patients must have been on a consis- tent skin care program for at least 1 month prior to enrollment and agreed to continue this regimen for the entire study.

Key exclusion criteria included more than 2 facial nodules, use of topical antiacne preparations on the face (including over-the-counter acne cleansers or treatments, retinoids, and light treatments), and use of systemic antiacne medica- tions (including corticosteroids, antibiotics, spironolactone, and retinoid therapy). An exclusion criterion of participation

in a prior clascoterone clinical trial was added to study CB-03- 01/25 owing to oversight in the initial protocol. No other changes in the conduct of the studies occurred. Full inclu- sion and exclusion criteria are listed in the study protocols (Supplements 1and2).

The safety set included all patients who received at least 1 application of the test article. The intent-to-treat (ITT) set included all randomized patients. The per-protocol (PP) set was a subset of the ITT population and included patients who completed the study without any significant protocol deviations. The Figure 1. Proposed Mechanism of Action of Clascoterone

A Cutibacterium acnes colonization

Inflammation

Epithelial keratinization

Excessive sebum production

B Sebaceous gland

Sebocytes

C Sebocyte cytosol

Nucleus

DHT

Androgen receptor Sebum and cytokine production

D

DHT

Clascoterone

A, Acne is characterized by epithelial hyperkeratinization, excessive sebum production, Cutibacterium acnes colonization of the pilosebaceous unit, and inflammation.⁶B, Within the sebaceous gland, sebocytes convert precursor molecules into androgens including

dihydrotestosterone (DHT).^6,13 C, Within sebocytes, DHT binds to androgen receptors in the cytosol. On binding, the DHT-androgen receptor complex dimerizes and translocates to the nucleus.²²There, it influences transcription of genes involved in acne pathogenesis, including sebum and inflammatory cytokine production.^13,21D, Clascoterone, applied topically to the skin, binds to the androgen receptor with high affinity at the site of application, competing with DHT.^20,21,23Results from in vitro studies suggest it thereby limits the effect of DHT on transcription of genes that modulate sebum production and

inflammation.^21,24

(4)

analysis of safety was conducted on the safety set. The analysis of efficacy was conducted on both the ITT and PP sets, with the ITT set considered as the primary set for statistical analysis

Interventions

The study plan consisted of a screening/baseline visit (visit 1), follow-up after 4 and 8 weeks of treatment (visits 2 and 3), and a final visit (visit 4) at the end of the 12-week treatment pe- riod. Patients were instructed to apply approximately 1 g of clascoterone cream, 1%, to the entire face twice daily for 12 weeks.

Eligible patients were randomized using Datatrak One soft- ware to receive clascoterone cream, 1%, or vehicle cream in a 1:1 ratio. The randomization sequence was prepared by Data- trak using a permuted block design with a block size of 4. The clinical team, patients, investigator, monitors, and employ- ees of the study sites were blinded to treatment allocation. The vehicle cream was identical to clascoterone cream, 1%, in terms of color, consistency, and smell, and the creams were packed in identical blinded tubes.

Assessments

At all study visits, IGA was performed using a 5-point scale (Supplements 1and2). Manual counting of noninflammatory lesions, inflammatory lesions, and nodules was performed. Five digital color photographs of each patient’s face (with the patient looking straight ahead, up, down, left, and right) were taken.

Local and systemic adverse events (AEs) and local skin reactions (LSRs) (ie, telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling/dryness, stinging/burning, pruritus) were evaluated at each study visit. Investigators assessed LSRs using a 5-point scale (0, none; 1, trace; 2, mild; 3, moderate; 4, severe). Patients rated severity of stinging or burning and pruritus on a 4-point scale (0, none; 1, mild; 2, moderate; 3, severe) at each study visit. Electrocardiograms (ECGs) taken at visits 1 and 4 were assessed by a central reviewer (ie, cardiologist).

Treatment compliance was evaluated at each visit and overall according to the formula: 100 × (number of actual applications/numbers of scheduled applications). Noncompli- ance was defined as a compliance value less than 80%.

The amount of product used (grams applied) was calculated from the weights of the returned tubes. The mean daily amount of product applied (total amount of product used/

number of days of treatment) was calculated for each patient.

Main Outcome Measures

Three coprimary efficacy end points were assessed in hierar- chal order: proportion of patients achieving treatment success at week 12, absolute change from baseline in noninflammatory lesion count (NILC), and inflammatory lesion count (ILC) at week 12. Treatment success was defined as at least a 2-point reduction in IGA score from baseline and a score of clear (0) or almost clear (1).

Secondary efficacy end points for both studies included percentage change from baseline in total lesion count (TLC), NILC, ILC at week 12, and absolute change from baseline in TLC at week 12. Safety end points for both studies included local and systemic AEs, LSRs, changes in ECGs at week 12, and results of urine pregnancy tests.

Statistical Analysis

Based on assumptions estimated from the phase 2 dose- escalation study (NCT01631474), at least 350 patients in each treatment arm in each study were required to provide sufficient power (90%) with the selected primary end points. No interim analyses were planned or performed. All statistical analysis was performed using SAS, version 9.3 (SAS Institute).

A logistic regression model with treatment and analysis center as fixed effects was used to compare the proportion of patients achieving treatment success at week 12. Adjusted odds ratio with associated 95% CIs were analyzed. Analysis of the re- maining primary and secondary efficacy end points was performed using an analysis of covariance model, with treatment and analysis center as fixed effects and baseline value as the co- variate. Adjusted least squares means with associated 95% CIs of difference from the analysis of covariance model were analyzed. Sensitivity analyses were performed to investigate the robustness of the results obtained on the ITT set for the primary efficacy end points. All AEs were coded using the Medi- cal Dictionary for Regulatory Activities, version 18.1.

The multiple imputation method under the missing at ran- dom assumption was used to impute missing values for the primary end points and absolute change in total lesions count in the ITT analyses. Sensitivity analyses were performed to investigate the robustness of the results obtained in the ITT set for the primary end points (change from baseline in NILC and ILC and IGA).

Results

Patients

In study CB-03-01/25, the first patient was enrolled on Janu- ary 21, 2016, and the last patient completed the study on April 11, 2018. In study CB-03-01/26, the first patient was enrolled on November 16, 2015, and the last patient completed the study on February 21, 2018.

In study CB-03-01/25, 708 patients were randomized; 353 were assigned to treatment with clascoterone cream, 1%, and 355 to vehicle cream. In study CB-03-01/26, 732 patients were randomized; 369 received clascoterone cream, 1%, and 363 received vehicle cream. Figure 2 shows the enrollment and outcomes for participants. All enrolled patients received at least 1 application of product and were included in the ITT and safety sets.

Patient baseline demographic and clinical characteristics are presented in Table 1. Characteristics were balanced between treatment arms in both studies.

Treatment Exposure

The majority of patients in both trials were treatment compliant (≥80% of expected cream application at each study visit).

In CB-03-01/25, the mean (SD) daily amount of product used in the ITT/safety population was 1.96 (0.60) g of clascoterone cream, 1%, and 1.96 (0.58) g of vehicle; 316 of 353 (89.5%) patients receiving clascoterone cream, 1%, and 310 of 355 (87.3%) patients receiving vehicle were treatment compliant. For CB-03-01/26, the mean (SD) daily amount of product used was

(5)

1.97 (0.51) g for clascoterone cream, 1%, and 1.98 (0.51) g for vehicle, with treatment completed in 340 of 369 (92.1%) patients and 313 of 363 (86.2%) patients, respectively.

Efficacy

Both trials met the primary efficacy end points. Considerably more patients receiving clascoterone cream, 1%, vs vehicle Table 1. Baseline Demographic and Clinical Characteristics of Patients

in Studies CB-03-01/25 and CB-03-01/26

Characteristic

Studies, No. (%)

CB-01-01/25 CB-03-01/26

Clascoterone (n = 353)

Vehicle (n = 355)

Vehicle (n = 363) Sex

Male 132 (37.4) 140 (39.4) 126 (34.1) 142 (39.1)

Female 221 (62.6) 215 (60.6) 243 (65.9) 221 (60.9)

Age, median (range), y 18.0 (10-58) 18.0 (9-50) 18.0 (10-50) 18.0 (11-42)

Race

White 298 (84.4) 297 (83.7) 357 (96.7) 348 (95.9)

Asian 9 (2.5) 10 (2.8) 0 4 (1.1)

Black or African American 31 (8.8) 38 (10.7) 7 (1.9) 6 (1.7)

Other 15 (4.2) 10 (2.8) 5 (1.4) 5 (1.4)

Fitzpatrick skin type

I 7 (2.0) 7 (2.0) 7 (1.9) 12 (3.3)

II 111 (31.4) 111 (31.3) 122 (33.1) 107 (29.5)

III 122 (34.6) 121 (34.1) 170 (46.1) 166 (45.7)

IV 63 (17.8) 64 (18.0) 57 (15.4) 54 (14.9)

V 27 (7.6) 23 (6.5) 7 (1.9) 21 (5.8)

VI 23 (6.5) 29 (8.2) 6 (1.6) 3 (0.8)

Baseline IGA score

3 (moderate) 292 (82.7) 291 (82.0) 305 (82.7) 313 (86.2)

4 (severe) 61 (17.3) 64 (18.0) 64 (17.3) 50 (13.8)

TLC, mean (SD) 101.5 (25.12) 103.6 (26.13) 105.7 (25.76) 104.6 (24.18)

NILC, mean (SD) 59.1 (22.19) 60.7 (22.09) 62.8 (21.37) 63.3 (20.52)

ILC, mean (SD) 42.4 (11.77) 42.9 (12.31) 42.9 (12.20) 41.3 (10.96)

Abbreviations: IGA, Investigator’s Global Assessment;

ILC, inflammatory lesion count;

NILC, noninflammatory lesion count;

TLC, total lesion count.

Figure 2. CONSORT Diagrams

756 Screened patients

24 Screening failures 732 Randomized patients

369 Given clascoterone, 1% 363 Given vehicle

302 Completed 282 Completed

Study CB-03-01/26 B

81 Discontinued 37 Withdrew

5 Had poor compliance 24 Lost to follow-up

8 Had adverse reactions

1 Had lack of efficacy 4 Were withdrawn by

parent/guardian 1 Pregnancy 1 Other 825 Screened patients

117 Screening failures 708 Randomized patients

353 Given clascoterone, 1% 355 Given vehicle

287 Completed 290 Completed

Study CB-03-01/25 A

66 Discontinued 39 Lost to follow-up

2 Were withdrawn by parent/guardian 21 Withdrew

3 Had adverse reactions 1 Had progressive disease

65 Discontinued 32 Lost to follow-up

3 Were withdrawn by parent/guardian 15 Withdrew

6 Had adverse reactions

2 Were noncompliant with study drug 3 Had lack of efficacy

2 Other

1 Decided by physician 1 Pregnancy

67 Discontinued 30 Withdrew

3 Had lack of efficacy 24 Lost to follow-up

5 Were withdrawn by parent/guardian 2 Had adverse reactions 1 Had poor compliance 1 Decided by physician 1 Had progressive disease

(6)

achieved treatment success at week 12 (CB-03-01/25, 18.4% vs 9.0%; and CB-03-01/26, 20.3% vs 6.5%, respectively). The absolute change from baseline in NILC and ILC at week 12 were also substantially greater with use of clascoterone cream, 1%

vs vehicle (Table 2).

Secondary efficacy end points were also met, with considerably greater absolute change from baseline to week 12 in TLC, and percentage change from baseline to week 12 in NILC, ILC, and TLC (Table 2). Representative patient photographs at baseline (Figure 3A, C, and E) and week 12 (Figure 3B, D, and F) are shown.

Planned sensitivity analyses were performed to investigate the robustness of the results obtained from the ITT population for the 3 primary efficacy end points. The PP population included patients who completed the studies without major protocol deviation (270 patients assigned to clascoterone cream, 1%, and 260 to vehicle in CB-03-01/25, and 286 patients assigned to clascoterone cream, 1%, and 268 to vehicle in CB-03-01/26). Statistical significance for all 3 primary efficacy end points was retained in both trials when tested in the PP population, and all other sensitivity analyses also con- firmed the results obtained in the ITT population.

Safety

Overall, clascoterone was well tolerated and demonstrated a similar safety profile to that of vehicle (Table 2). The most common treatment emergent AEs (TEAEs) in studies CB-03-01/25 and CB-03-01/26 were nasopharyngitis, headache, and oropharyngeal pain.

TEAEs (n = 4) considered related to use of clascoterone cream, 1%, in study CB-03-01/25 were application site pain, oropharyngeal pain, application site dryness, and application site hypersensitivity (all mild in severity). In study CB-03-01/26, TEAEs (n = 9) considered related to clascoterone cream were application site dryness, application site erythema, application site hypertrichosis, acne, dermatitis contact, hair color changes, eye irritation, peritonsillar abscess, and headache.

The majority of TEAEs in both studies were mild or moderate in severity. Two patients receiving vehicle cream in CB-03-01/25 experienced severe TEAEs of pneumonia and application site acne, and 1 patient receiving vehicle cream in CB-03-01/26 experienced a severe TEAE of contusion. There were no severe TEAEs in patients treated with clascoterone.

One patient in each study assigned to receive vehicle cream experienced a serious TEAE (severe hematoma of the right thigh in CB-03-01/26 and severe pneumonia in CB-03-01/25), neither of which was considered related to study treatment or led to study discontinuation. No deaths were reported in either study.

Seventeen patients discontinued due to TEAEs: 5 receiving clascoterone cream, 1% (CB-03-01/25, 3 of 353 [0.8%]; and CB-03-01/26, 2 of 369 [0.5%]), and 12 receiving vehicle cream (CB-03-01/25, 4 of 353 [1.1%]; and CB-03-01/26, 8 of 369 [2.2%]).

TEAEs leading to discontinuation of clascoterone use included application site hypersensitivity, oropharyngeal pain, sebaceous hyperplasia, facial acute contact dermatitis, and depigmented hair on the nose (n = 1 for each); all were mild in severity.

In both studies, the proportion of subjects with each LSR was similar for both treatment groups throughout the study.

The majority of patients in each treatment group remained free of most LSRs throughout both studies.

The most frequently observed new or worsening LSRs for both CB-03-01/25 and CB-03-01/26 were erythema (clascoterone arm: 38 of 335 [11.3%]) and 46 of 352 [13.1%], respectively; vehicle arm: 52 of 332 [15.7%] and 49 of 330 [14.8%], respectively), and scaling/dryness (clascoterone arm: 41 of 335 [12.2%]) and 31 of 352 [8.8%], respectively; vehicle arm: 43 of 332 [13.0%] 25 of 330 [7.6%]), respectively), with most being minimal-mild in severity (clascoterone arm: 34 of 335 [10.1%]

and 39 of 352 [11.1%], respectively; vehicle arm: 45 of 332 [13.6%] and 43 of 330 [13.0%], respectively). There was 1 case of severe new or worsening erythema in the vehicle group in CB-03-01/25. Minimal-mild scaling/dryness occurred among arms in CB-03-01/25 and CB-03-01/26 (clascoterone arm: 39 of 335 [11.6%] and 31 of 352 [8.8%], respectively; vehicle arm:

43 of 332 [13.0%] and 25 of 330 [7.6%], respectively). There were no severe cases of scaling/dryness; however, there were 2 cases of moderate scaling/dryness in the CB-03-01/25 clascoterone arm and 1 in the vehicle arm of CB-03-01/26. Occurrence of mild pruritus was similar in both CB-03-01/25 and CB-03-01/26 (clascoterone arm: 17 of 335 [5.1%] and 19 of 352 [5.4%], respectively; vehicle arm: 20 of 332 [6.0%] and 17 of 330 [5.2%]), respectively). One severe pruritus case occurred in each study clascoterone arm, and 3 occurred in the vehicle arms (1 in CB-03-01/25 and 2 in CB-03-01/26). Moderate pruritus also occurred in CB-03-01/25 and CB-03-01/26 (clascoterone arm:

4 of 335 [1.2%] and 10 of 352 [2.8%], respectively; vehicle arm:

6 of 332 [1.8%] and 9 of 330 [2.7%], respectively). New or worsening telangiectasia, skin atrophy, edema, striae rubrae, and stinging/burning occurred at lower frequencies than erythema, scaling/dryness and pruritus, and if present, were predominantly trace-mild or minimal.

No substantial changes in ECGs were observed in either treatment group in either study. In each study, 1 patient assigned to vehicle became pregnant. In CB-03-01/25, a woman receiving vehicle had a positive pregnancy test at visit 3. She was discontinued from the study and lost to follow-up. In CB-03-01/26, a woman received vehicle treatment for 9 days, then discontinued the treatment before pregnancy confirma- tion. The neonate was born preterm but “fine” at 35 weeks. No other details were available.

Discussion

The results of these 2 identical phase 3 studies demonstrate that clascoterone cream, 1%, applied topically twice daily for 12 weeks, is considerably more effective than application of vehicle cream at achieving IGA success and reducing NILC and ILC in patients with facial acne vulgaris. No safety concerns were noted during these studies, and clascoterone cream, 1%, was well tolerated.

Together, these 2 studies enrolled 1440 patients with acne between the ages of 9 and 58 years. Treatment adherence was approximately 90% for patients applying clascoterone cream,

(7)

Table 2. Efficacy and Safety Results From Studies CB-03-01/25 and CB-03-01/26

Conclusions

In conclusion, clascoterone cream, 1%, is a topical androgen receptor inhibitor with a novel mechanism of action for acne

treatment. The 2 phase 3 trials assessed here demonstrate the safety and efficacy of clascoterone cream, 1%, in patients 9 years and older who have facial acne vulgaris. Clascoter- one cream, 1%, is under consideration as a first-in-class therapeutic agent for acne treatment, potentially providing an alternative to antibiotics and/or offering an adjunct treatment to existing combination acne therapies, including retinoids.

ARTICLE INFORMATION

Accepted for Publication: March 4, 2020.

Published Online: April 22, 2020.

Author Contributions: Dr Mazzetti had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Thiboutot, Cartwright, Gerloni, Fragasso, Mazzetti.

Acquisition, analysis, or interpretation of data:

Hebert, Thiboutot, Stein Gold, Cartwright, Fragasso, Mazzetti.

Drafting of the manuscript: Cartwright, Fragasso, Mazzetti.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Mazzetti.

Administrative, technical, or material support:

Cartwright, Gerloni, Mazzetti.

Study supervision: Hebert, Stein Gold, Cartwright, Fragasso, Mazzetti.

Conflict of Interest Disclosures: Drs Hebert, Thiboutot, and Stein Gold were study investigators and are compensated (ie, honoraria, personal fees) advisors to Cassiopea. Dr Hebert is an employee of the McGovern Medical School of The University of Texas Health Science Center in Houston, which received compensation from Cassiopea SpA for study participation; she also received honorarium for serving on the Cassiopea advisory board.

Dr Stein Gold is an employee of the Henry Ford Health System in Detroit, Michigan, which received compensation from Cassiopea SpA for study participation; she has also received personal fees for advisory, speaking, consulting, research, and/or other ties with Almirall, Foamix, Galderma Laboratories, Novartis, Sol-Gel, and Sun Pharmaceuticals. Dr Thiboutot is an employee of the College of Medicine at The Pennsylvania State University in Hershey, which received

compensation from Cassiopea SpA for study participation; she has also received grants and honoraria from Botanix, Galderma Laboratories, and Novartis. Dr Cartwright is employed as the senior director of medical affairs for Cassiopea Inc and received personal fees as a consultant to Cassiopea SpA; receives personal fees as an adjunct faculty member at the University of Arizona; holds stock options in Cassiopea SpA; and previously was a contracted employee of Anacor-Pfizer and consultant to Menlo Therapeutics, NICO Corporation, and Abbott Nutrition. Dr Gerloni is an employee and officer of Bellatrix Pharmaceuticals, a subsidiary of Cosmo Pharmaceuticals, the parent company of Cassiopea SpA and Cassiopea Inc, and is a research consultant to Cassiopea SpA.

Mr Fragasso is employed as the clinical project manager for Cassiopea SpA and holds stock options in the company. Dr Mazzetti is employed as the chief medical officer for Cassiopea SpA and holds stock options in the company, is a board member of Cassiopea SpA, and has served as the chief medical officer for Cosmo Pharmaceuticals.

Funding/Support: Preparation of this manuscript and conduct of the clinical trials were funded by Cassiopea SpA.

Role of the Funder/Sponsor: Cassiopea SpA was responsible for the design and conduct of the studies; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript and decision to submit the manuscript for publication.

Additional Contributions: The authors thank Anne Carter, MA(Cantab), of medicalwriters.com in Zurich, Switzerland, for providing medical writing support, which was funded by Cassiopea SpA in Milan, Italy, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/

gpp3). The authors also thank Caridad Rosette, PhD, of Bellatrix Pharmaceuticals for the mechanism of action experimental studies, Cross Metrics SA of Mendrisio, Switzerland, for conducting the statistical analyses, Larry Shen, PhD, of Pharmapace Inc for providing additional statistical support and interpretation, and Roberta Macis, MS, for her assistance with data retrieval.

Data Sharing Statement: SeeSupplement 3.

REFERENCES

1. Tan JK, Bhate K. A global perspective on the epidemiology of acne. Br J Dermatol. 2015;172(suppl 1):3-12. doi:10.1111/bjd.13462

2. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2163-2196. doi:10.

1016/S0140-6736(12)61729-2

3. Lynn DD, Umari T, Dunnick CA, Dellavalle RP.

The epidemiology of acne vulgaris in late adolescence. Adolesc Health Med Ther. 2016;7:13-25.

doi:10.2147/AHMT.S55832

4. Rocha MA, Bagatin E. Adult-onset acne:

prevalence, impact, and management challenges.

Clin Cosmet Investig Dermatol. 2018;11:59-69.

doi:10.2147/CCID.S137794

5. Leyden JJ, Del Rosso JQ, Baum EW. The use of isotretinoin in the treatment of acne vulgaris:

clinical considerations and future directions.J Clin Aesthet Dermatol. 2014;7(2)(suppl):S3-S21.

6. Moradi Tuchayi S, Makrantonaki E, Ganceviciene R, Dessinioti C, Feldman SR, Zouboulis CC. Acne vulgaris. Nat Rev Dis Primers. 2015;1:15029. doi:10.

1038/nrdp.2015.29

7. Hauk L. Acne vulgaris: treatment guidelines from the AAD.Am Fam Physician. 2017;95(11):

740-741.

8. Thiboutot DM, Dréno B, Abanmi A, et al Practical management of acne for clinicians: an international consensus from the Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2018;78(2) (suppl 1):S1-S23.e1.

9. Zaenglein AL, Pathy AL, Schlosser BJ, et al.

Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945-73.e33.

doi:10.1016/j.jaad.2015.12.037

10. Adler BL, Kornmehl H, Armstrong AW.

Antibiotic resistance in acne treatment. JAMA Dermatol. 2017;153(8):810-811. doi:10.1001/

jamadermatol.2017.1297

11. Layton A. The use of isotretinoin in acne.

Dermatoendocrinol. 2009;1(3):162-169. doi:10.4161/

derm.1.3.9364

12. Elsaie ML. Hormonal treatment of acne vulgaris:

an update. Clin Cosmet Investig Dermatol. 2016;9:

241-248. doi:10.2147/CCID.S114830 13. Dart DA. Androgens have forgotten and emerging roles outside of their reproductive functions, with implications for diseases and disorders. J Endocr Disord. 2014;1(1):1005.

14. Lai JJ, Chang P, Lai KP, Chen L, Chang C.

The role of androgen and androgen receptor in skin-related disorders. Arch Dermatol Res. 2012;

304(7):499-510. doi:10.1007/s00403-012- 1265-x

15. Estrostep Fe. Prescribing information. Allergan Inc; 2017.

16. Ortho-cyclen and Ortho tri-cyclen. Prescribing information. Janssen Pharmaceutical Inc; 2017.

17. Huber J, Walch K. Treating acne with oral contraceptives: use of lower doses. Contraception.

2006;73(1):23-29. doi:10.1016/j.contraception.2005.

07.010

18. Aldactone. Prescribing information. Pfizer Inc;

2018.

19. Layton AM, Eady EA, Whitehouse H, Del Rosso JQ, Fedorowicz Z, van Zuuren EJ. Oral spironolactone for acne vulgaris in adult females:

a hybrid systematic review. Am J Clin Dermatol.

2017;18(2):169-191. doi:10.1007/s40257-016- 0245-x

20. Ferraboschi P, Legnani L, Celasco G, Moro L, Ragonesi L, Colombo D. A full conformational characterization of antiandrogen

cortexolone-17α-propionate and related compounds through theoretical calculations and nuclear magnetic resonance spectroscopy.

MedChemComm. 2014;5:904-914. doi:10.1039/

C4MD00049H

21. Rosette C, Agan FJ, Mazzetti A, Moro L, Gerloni M. Cortexolone 17α-propionate (clascoterone) is a

(10)

novel androgen receptor antagonist that inhibits production of lipids and inflammatory cytokines from sebocytes in vitro.J Drugs Dermatol. 2019;18 (5):412-418.

22. Tan MH, Li J, Xu HE, Melcher K, Yong EL.

Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin.

2015;36(1):3-23. doi:10.1038/aps.2014.18 23. Celasco G, Moro L, Bozzella R, et al. Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist.Arzneimittelforschung.

2004;54(12):881-886.

24. Rosette C, Rosette N, Mazzetti A, Moro L, Gerloni M. Cortexolone 17α-propionate

(clascoterone) is an androgen receptor antagonist in dermal papilla cells in vitro.J Drugs Dermatol.

2019;18(2):197-201.

25. Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G. Cortexolone 17α-propionate 1%

cream, a new potent antiandrogen for topical treatment of acne vulgaris: a pilot randomized, double-blind comparative study vs. placebo and tretinoin 0·05% cream. Br J Dermatol. 2011;165(1):

177-183. doi:10.1111/j.1365-2133.2011.10332.x 26. Mazzetti A, Moro L, Gerloni M, Cartwright M.

Pharmacokinetic profile, safety, and tolerability of clascoterone (cortexolone 17-alpha propionate, CB-03-01) topical cream, 1% in subjects with facial acne vulgaris: an open-label phase 2a study.J Drugs Dermatol. 2019;18(6):563-568.

27. Mazzetti A, Moro L, Gerloni M, Cartwright M.

A phase 2b, randomized, double-blind vehicle controlled, dose escalation study evaluating clascoterone 0.1%, 0.5%, and 1% topical cream in subjects with facial acne.J Drugs Dermatol. 2019;18 (6):570-575.

28. US Food and Drug Administration Center for Drug Evaluation and Research. Guidance for industry: acne vulgaris: developing drugs for treatment. September 19, 2005. Accessed March 23, 2020.https://www.federalregister.gov/

documents/2005/09/19/05-18512/draft-guidance- for-industry-on-acne-vulgaris-developing-drugs- for-treatment-availability.